The present invention is concerned with new ethers of .gamma.-cyclodextrin, their preparation and their use as complexants for chemicals and pharmaceuticals.
.gamma.-cyclodextrin (.gamma.-CD) is a cyclic oligosaccharide consisting of 8 glucose units which are joined together by .alpha.(1-4) linkages. ##STR1## .gamma.-CD is prepared by the enzymatic cleavage and religation of starch and a subsequent separation from the thus obtained cyclodextrin mixture containing i.a. .alpha.-cyclodextrin (containing 6 glucose units), .beta.-cyclodextrin (.beta.-CD) (7 glucose units) and .gamma.-cyclodextrin (.gamma.-CD).
Cyclodextrins are known in the art to possess the ability to form inclusion complexes and to have concomitant solubilizing properties. An exhaustive review which describes such complexes and their properties can be found in W. Sanger, Angewandte Chemie, 92, 343-361 (1981).
Derivatives of cyclodextrins are also known to possess the above-mentioned properties. Said derivatives have been reviewed in an article by A. P. Croft and R. A. Bartsch in Tetrahedron, 39, 1417-1474 (1983). More particularly, the German Offenlegungsschrift DE No. 3118218 discloses the 2,6-dimethyl derivatives of .beta.-CD, while in U.S. Pat. No. 3,459,731 there are described hydroxyethyl, hydroxypropyl and hydroxypropyl/hydroxyethyl ethers of .beta.-CD. Furthermore, in U.S. patent application Ser. No. 6-603, 839 there is described the use of specific derivatives of cyclodextrines to improve the systemic administration of sex hormones. Most of the cyclodextrin derivatives presently known in the art are derived from .beta.-CD, while the derivatives of .alpha.-CD and particularly of .gamma.-CD remain relatively unknown.
The use of derivatives of .beta.-CD has the following advantages. .beta.-CD is only poorly water soluble and therefore it is disadvantageous to use it as a complexant and solubilizer. Derivatives of .beta.-CD on the other hand, due to their increased solubility, are more suitable complexants and solubilizers. In contrast herewith, .alpha.-CD and .gamma.-CD having an excellent water solubility do not need such substitutions. Hence, it is obvious to use unsubstituted .gamma.-CD (and .alpha.-CD) as complexant and solubilizer. Particularly for .gamma.-CD, a number of such complexes with various useful compounds can be found in e.g. Int. J. Pharm. 10, 1-15 (1982) with steroid hormones, in Acta Pharm. Suec. 20, 11-20 (1983) with flurtripofen, in Chem. Pharm. Bull. 31, 286-291 (1983) with spirolacton and in Acta Pharm. Suec. 20, 287-294 (1983) with proscillaridin.
.gamma.-CD does not form such inclusion complexes with any given compound. Often, such complexation is onlyu established in the lower concentration range. At higherr concentrations of .gamma.-CD, the formed complex is precipitated.
It has now been found that an appropriately alkylated, hydroxyalkylated, carboxyalkylated or (alkyloxycarbonyl)alkylated form of .gamma.-CD or a mixed ether thereof prevents the crystallization of such complexes. The advantages of .gamma.-CD over its lower homologues, i.e. its larger cavity resulting in a superior propensity to form inclusion complexes, its favourable toxicological properties and the fact that it can be cleaved enzymatically by .alpha.-amylase (in contrast with .beta.-CD), can therefore fully be exploited.
.gamma.-CD contains three free hydroxy functions per glucose unit which can completely or partially be derivatized. In view of this, the average degree of substitution (D.S.) is introduced, which is the average number of substituted hydroxy functions per glucose unit. Said D.S. can vary from its minimal value 0.125 up to its maximal value 3. In the latter case all 24 hydroxy groups are substituted, while in the former case only one is substituted. A minimal D.S. is especially preferred when .gamma.-CD is used as solubilizer of pharmaceuticals for use in parenteral applications, while a higher D.S. is preferred when used in technical applications, such as, for example, for pesticides or enzymes. In the latter instance, the higher D.S. causes that also those hydroxy groups are functionalized which are located in the cavity of the .gamma.-CD molecule. Consequently, the diameter of the cavity is decreased. By selecting the appropriate D.S. the size of the cavity can be adapted in order to obtain the optimum space required for a certain molecule to appropriately fit into the cavity of the cyclodextrin.
When introducing hydroxyalkyl substitutions on .gamma.-CD, the hydroxy function of the thus obtained hydroxyalkyl ether group can further be hydroxyalkylated, generating multiple substitutions on one particular OH-group. In such cases the term average molar substitution (M.S.) is introduced. Said M.S. is defined as the average number of moles of the substituting agent per glucose unity. In view of this, it is evident that the M.S. can be greater than 3 and has, theoretically, no upper limit.